on November 11, 2004
Published online before print November 11, 2004, doi: 10.1161/01.ATV.0000150041.81963.68
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on June 19, 2004
Accepted on October 20, 2004
Protein Kinase C Pathway Is Involved in Transcriptional Regulation of C-Reactive Protein Synthesis in Human Hepatocytes
Yuri Ivashchenko ;
From the Aventis Pharma Deutschland GmbH (Y.I., F.K., K.V., A. Busch, O.R., J.D.), DG Cardiovascular Research, Frankfurt am Main; and the Department of Internal Medicine II-Cardiology (S.S., A. Bucher, V.H., J.T.), University of Ulm, Germany.
* To whom correspondence should be addressed. E-mail: jan.torzewski{at}medizin.uni-ulm.de.
Objective--C-Reactive protein (CRP) is the prototype acute phase protein and a cardiovascular risk factor. Interleukin-1
(IL-1) and IL-6 stimulate CRP synthesis in hepatocytes. We searched for additional pathways regulating CRP expression.
Methods and Results--Primary human hepatocytes (PHHs) were treated with IL-1, IL-6, and protein kinase C (PKC) activator phorbol 12,13-dibutyrate (PDBu). CRP was analyzed by quantitative RT-PCR and ELISA. PDBu significantly induced CRP transcription by 21.0±9.24-fold and protein release by 2.9±0.5-fold. Transcriptional regulation was studied in detail in hepatoma G2 (HepG2) cells stably transfected with the 1-kb CRP promoter (HepG2-ABEK14 cells). In these cells, PDBu significantly induced CRP transcription by 5.39±0.66-fold. Competetive inhibition with bisindolylmaleimide derivative LY333531 abolished PDBu-mediated promoter activation. Competetive inhibition with I
B kinase inhibitor I229 also inhibited PDBu effects. Importantly, IL-8 significantly induced CRP release in PHHs by 58.675±19.1-fold, which was blockable by LY333531.
Conclusions--This study describes a novel PKC-dependent transcriptional regulation of CRP gene expression, which, in analogy to the classical IL-1 and IL-6 pathways, is operational in hepatocytes only. It also identifies IL-8 as a potential physiological PKC activator. HepG2-ABEK14 cells may be useful for high throughput screening to identify inhibitors of CRP synthesis for the prevention of cardiovascular disease.
Key words: atherosclerosis • C-reactive protein • drug development • gene expression • protein kinase C
This article has been cited by other articles:
 |
|
 |
|
  J. Shen and J. M. Ordovas Impact of Genetic and Environmental Factors on hsCRP Concentrations and Response to Therapeutic Agents Clin. Chem., February 1, 2009; 55(2): 256 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. N. Patel, C. A. King, S. R. Bailey, J. W. Holt, K. Venkatachalam, A. Agrawal, A. J. Valente, and B. Chandrasekar Interleukin-17 Stimulates C-reactive Protein Expression in Hepatocytes and Smooth Muscle Cells via p38 MAPK and ERK1/2-dependent NF-{kappa}B and C/EBPbeta Activation J. Biol. Chem., September 14, 2007; 282(37): 27229 - 27238. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Blaschke, Y. Takata, E. Caglayan, A. Collins, P. Tontonoz, W. A. Hsueh, and R. K. Tangirala A Nuclear Receptor Corepressor-Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor Circ. Res., December 8, 2006; 99(12): e88 - e99. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Crawford, C. L. Sanders, X. Qin, J. D. Smith, C. Shephard, M. Wong, L. Witrak, M. J. Rieder, and D. A. Nickerson Genetic Variation Is Associated With C-Reactive Protein Levels in the Third National Health and Nutrition Examination Survey Circulation, December 5, 2006; 114(23): 2458 - 2465. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Sun, T. Koike, T. Ichikawa, K. Hatakeyama, M. Shiomi, B. Zhang, S. Kitajima, M. Morimoto, T. Watanabe, Y. Asada, et al. C-Reactive Protein in Atherosclerotic Lesions: Its Origin and Pathophysiological Significance Am. J. Pathol., October 1, 2005; 167(4): 1139 - 1148. [Abstract] [Full Text] [PDF]
|
|